Abstract

Some carcinogenic, mutagenic, and biochemical properties of dl-ethionine and S-vinyl-dl-homocysteine (vinthionine) were compared to examine a possible role of vinthionine as a proximate carcinogenic metabolite of ethionine. Both dl-amino acids induced hepatic carcinomas in essentially all of the male Fischer rats fed these structurally similar compounds for 16 to 20 months as 0.1% of a 16% casein, choline-supplemented diet; the tumors appeared sooner in the rats fed ethionine than in those fed vinthionine. Administration in a methyl-deficient diet facilitated dl-ethionine-induced carcinogenesis more than dl-vinthionine-induced carcinogenesis. Multiple i.p. injections over a 12-week period of dl-vinthionine (total dose, 7 mmol/kg body weight) induced hepatocellular carcinomas in 9 of 28 and 6 of 28 male Fischer rats, respectively, that were or were not subsequently treated with phenobarbital until the termination of the experiment at 25 months. dl-Ethionine had only marginal carcinogenic activity under these conditions. Approximately 50% of female CD-1 mice fed 0.1% of dl-vinthionine or dl-ethionine in the 16% casein, choline-supplemented diet developed hepatomas by 18 months; male CD-1 mice were less susceptible.

l- or dl-vinthionine, but not l-, d-, or dl-ethionine, was a strong direct mutagen for Salmonella typhimurium strain TA100. l-Vinthionine (16 revertants/nmol) was about 30% more mutagenic than the dl mixture was. dl-Vinthionine sulfoxide and N-acetyl-dl-vinthionine methyl ester were only weakly mutagenic. Of several compounds that interfere with the metabolism of ethionine or its carcinogenic activity, only l-methionine (1000 nmol/plate) completely protected strain TA100 against the mutagenic activity of l-vinthionine (60 nmol/plate).

Administration of a single i.p. dose of dl-vinthionine (1 g/kg body weight) to rats caused a reduction in the hepatic level of adenosine triphosphate, but dl-vinthionine was less effective than dl-ethionine. However, attempts to demonstrate the accumulation of S-adenosylvinthionine in the livers of vinthionine-treated rats or mice or as a product of l-vinthionine with an adenosine triphosphate-supplemented yeast extract capable of converting either dl-methionine or dl-ethionine to their S-adenosyl derivatives were unsuccessful.

After a single i.p. injection, 14C from l-[vinyl-14C]vinthionine was bound to rat liver DNA, RNA, and protein. The magnitude of the binding to DNA (110 pmol/mg DNA 18 hr after a single i.p. injection of 31 mg/kg body weight) was of the order of that observed for strong hepatic carcinogens and much greater than the very low levels reported for l-[ethyl-3H or ethyl-14C] ethionine.

Footnotes

↵1 This work was supported by Grants CA-07175, CA-09135, and CA-22484 from the National Cancer Institute, USPHS.